Process to prepare n-[2-[(1s)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl) ethyl]-1, 3-dioxo-2,3-dihydro-1h-isoindol-4yl]acetamide

Abstract

An alternative and improved process for the preparation of Apremilast (Formula I) and Apremilast form B or a pharmaceutically acceptable salt thereof is provided. The novel process includes hydrogenation in acetone, Cyclization and acetylation followed by condensation in methyl isobutyl ketone (MIBK) and acetic acid mixture in specific volume ratios.

Claims

1. A process to prepare Apremilast form B comprising steps of; i. hydrogenation of 3-nitrobenzene-1, 2-dicarboxylic acid (Formula-II) in presence of suitable reducing agent and acetone as a solvent at a suitable temperature to prepare 3-aminobenzene-1, 2-dicarboxylic acid (Formula-III); ii. cyclization and acetylation of 3-aminobenzene-1, 2-dicarboxylic acid (Formula-III) obtained in step i) with acetic anhydride at suitable temperature to prepare N-(1, 3-dioxo-1, 3-dihydro-2-benzofuran-4-yl) acetamide (Formula-IV); iii. condensation of (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (Formula-V) and N-(1, 3-dioxo-1, 3-dihyro-2-benzofuran-4-yl) acetamide (Formula-IV) in presence of methyl isobutyl ketone (MIBK) and acetic acid mixture, wherein MIBK and acetic acid is in the ratio of 11:4 to 12:4.5 to prepare N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl) ethyl]-1, 3-dioxo-2,3-dihydro-1H-isoindol4-yl]acetamide (Formula-I); iv. crystallization of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl) ethyl]-1, 3-dioxo-2,3-dihydro-1H-isoindol4-yl]acetamide (Formula-I) prepared in step iii using a suitable solvent to obtain Apremilast Form B.

2. A process for preparation of Apremilast (Formula I) having less than 0.15% w/w of Des-acetyl impurity, the process comprising steps of: i. hydrogenation of 3-nitrobenzene-1, 2-dicarboxylic acid (Formula - II) in presence of suitable catalyst and acetone as a solvent to prepare 3-aminobenzene-1, 2-dicarboxylic acid (Formula -III); ii. cyclization and acetylation of 3-aminobenzene-1, 2-dicarboxylic acid (Formula- III) obtained in step i) with acetic anhydride to prepare N-(1, 3-dioxo-1, 3-dihydro- 2-benzofuran-4-yl) acetamide (Formula-IV); and iii. condensation of (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (Formula-V) and N-(1, 3-dioxo-1, 3dihyro-2-benzofuran-4-yl) acetamide (Formula-IV) in presence of methyl isobutyl ketone and acetic acid mixture, wherein MIBK and acetic acid is in the ratio of 11:4 to 12:4.5 to prepare Apremilast (Formula I) having less than 0.15% w/w by HPLC of Des-acetyl impurity.

3. The process as claimed in claim 1 wherein in step i, the reducing agent is 10% Palladium on carbon, or Raney nickel, and the hydrogenation is carried out at temperature range of 5 C. to 25 C.

4. The process as claimed in claim 1 wherein the Cyclization and acetylation of 3-aminobenzene-1, 2-dicarboxylic acid is carried out at temperature range of 90 C. to 140 C.

5. The process as claimed in claim 1, wherein suitable solvent for crystallization in step iv is selected from acetone, ethanol and mixture thereof.

6. A process of hydrogenation of 3-nitrobenzene-1, 2-dicarboxylic acid (Formula - II) to prepare 3-aminobenzene-1, 2-dicarboxylic acid (Formula -III) in the presence of catalyst using Acetone as a solvent.

7. The process as claimed in claim 6, wherein the catalyst is selected from 10% Palladium on carbon and Raney Nickel.

8. The process as claimed in claim 2 wherein in step i, the catalyst is 10% Palladium on carbon or Raney nickel, and the hydrogenation is carried out at temperature range of 5 C. to 25 C.

9. The process as claimed in claim 2 wherein the Cyclization and acetylation of 3-aminobenzene-1, 2-dicarboxylic acid is carried out at a temperature range of 90 C. to 140 C.

Description

EXAMPLES

Example 1

Preparation of 3-Aminobenzene-1, 2-Dicarboxylic acid or 3-Amino Phthalic Acid (Formula-III)

(1) 3-Nitrobenzene-1,2-dicarboxylic acid or 3-Nitro Phthalic acid (Formula -II) (200 gm) and 10% Pd/C (10 gm) in acetone (2400 ml) charge in autoclave and maintain hydrogen pressure of 3-4 kg/cm.sup.2 for 3 hr at 15-20 C. (15-25 C.) in autoclave. Filter reaction through hyflobed and distill out reaction mass completely. Charge ethyl acetate followed by n-hexane. Stir reaction mass for 2 hr at ambient temperature and filtered resulting Formula II with 95% yield and 94.98% HPLC purity.

(2) The reaction works well when the quantity of 10% Pd/C used is 5 gm and hydrogenation is completed.

Example 2

Preparation of 3-Aminobenzene-1, 2-Dicarboxylic Acid or 3-Amino Phthalic Acid (Formula-III)

(3) 3-Nitrobenzene-1,2-dicarboxylic acid or 3-Nitro Phthalic acid (Formula -II) (50 gm) and 10% Pd/C (5 gm) in ethanol (500 ml) charge in autoclave and maintain hydrogen pressure of 3-4 kg/cm.sup.2 for 1 hr at 15-20 C. (15-25 C.) in autoclave. Filter reaction through hyflobed and distill out reaction mass completely. Charge ethyl acetate followed by n-hexane. Stir reaction mass for 2 hr at ambient temperature and filtered resulting Formula II with 80% yield and 98.72% HPLC purity.

Example 3

Preparation of N-(1, 3-Dioxo-1, 3Dihyro-2-Benzofuran-4-Yl) Acetamide or 3-Acetamido-Phthalic Anhydride (Formula-IV)

(4) 3-Aminobenzene-1, 2-dicarboxylic acid or 3-Amino Phthalic acid (Formula-III) (150 gm) into acetic anhydride (525 ml) at 25-30 C. Raise temperature up to 130-140 C. and maintain 2 hr. After completion of reaction gradually cool to ambient temperature. Stir reaction mass for 2 hr and cool up to 0-5 C. (0-10 C.). Filter the product and wash with methyl tert. butyl ether resulting Formula IV with 78.6% yield and 99.49% HPLC purity.

Example 4

Chiral Purification of (1S)-1-(3-Ethoxy-4-Methoxy-Phenyl)-2-Methanesulfonyl-Ethylamine (Formula-V) by Crystallization

(5) Charge ethyl acetate (350 ml) and charge (1S)-1 -(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (Formula-V) (100 gm) at temperature 65-75 C., cool up to ambient temperature, filtered and wash with n-hexane: ethyl acetate mixture of solvent to get pure (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (Formula-V).

Example 5

Preparation of N-[2-[(1S)-1-(3-Ethoxy-4-Methoxyphenyl)-2-(Methylsulphonyl) Ethyl]-1, 3-Dioxo-2, 3-Dihydro-1H-Isoindol-4-yl] Acetamide (Formula-I)

(6) (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (Formula-V) (125 gm) and N-(1, 3-dioxo-1, 3dihyro-2-benzofuran-4-yl) acetamide (Formula-IV) (98.5 gm) in to methyl isobutyl ketone (1500 ml) and acetic acid (550 ml) mixture of solvent at ambient temperature. Raise temperature up to 115-120 C. (115-125 C.). Remove the water formed during the reaction. After completion of reaction distill out reaction mass completely. Charge ethyl acetate for extraction and wash with sodium bicarbonate solution and sodium chloride solution. Distill out reaction mass completely and charge acetone followed by ethanol. Raise temperature up to reflux and maintain 1 hr. Reaction gradually cool to ambient temperature and maintain reaction mass and stir for 7-8 hr. Filter the product and wash with ethanol. Charge wet cake into acetone followed by ethanol. Raise temperature up to reflux and maintain 1 hr. Reaction gradually cool to ambient temperature and maintain reaction mass and stir for 7-8 hr. Filter the product and wash with ethanol resulting Formula I with 73.1% yield and 99.98% HPLC purity and 99.99 Chiral purity. The titled product having XRPD values as, 10.1, 12.4, 13.5, 20.8, 22.5, 24.7, and 27.0 0.2 (Form-B).